Implantable or insertable medical devices for controlled drug delivery

ABSTRACT

Implantable or insertable medical devices are provided, which comprises: (a) a biocompatible polymer; and (b) at least one therapeutic agent selected from an anti-inflammatory agent, an analgesic agent, an anesthetic agent, and an antispasmodic agent. The medical devices are adapted for implantation or insertion at a site associated with pain or discomfort upon implantation or insertion. In many embodiments, the therapeutic will be selected from at least one of (i) ketorolac and pharmaceutically acceptable salts thereof (e.g., ketorolac tromethamine) and (ii) 4-diethylamino-2-butynylphenylcyclohexyl glycolate and pharmaceutically acceptable salts thereof (e.g., oxybutynin chloride). Also provided are uses for the implantable or insertable medical devices, which uses comprise reducing pain or discomfort accompanying the implantation or insertion of such devices. Further uses may comprise reducing microbial buildup along the device. Methods for manufacturing implantable or insertable medical devices are also provided.

RELATED APPLICATION DATA

This patent application is a continuation-in-part of U.S. Ser. No.10/209,476 filed Jul. 31, 2002 and entitled “CONTROLLED DRUG DELIVERY,”the disclosure of which is incorporated by reference.

This patent application is also a continuation-in-part of U.S. Ser. No.10/071,840 filed Feb. 8, 2002 now U.S. Pat. No. 6,887,270 and entitled“IMPLANTABLE OR INSERTABLE MEDICAL DEVICE RESISTANT TO MICROBIAL GROWTHAND BIOFILM FORMATION,” the disclosure of which is incorporated byreference.

TECHNICAL FIELD

This invention generally relates to medical devices, and moreparticularly to implantable or insertable medical devices and methodsfor their manufacture.

BACKGROUND INFORMATION

Numerous medical devices have been developed for the delivery oftherapeutic agents to the body. In accordance with some deliverystrategies, a therapeutic agent is provided within a polymeric matrixthat is associated with an implantable or insertable medical device.Once the medical device is placed at the desired location within apatient, the therapeutic agent is released from the polymeric matrix.

Various techniques, including thermoplastic processing techniques, havebeen used for the manufacture of medical devices for the delivery oftherapeutic agents to the body. However, many therapeutic agents areunstable under the processing conditions associated with suchtechniques. Accordingly, there is a continuing need for processingtechniques that do not result in substantial degradation of thetherapeutic agents, particularly those having low stability.

Numerous medical devices have also been developed for implantation orinsertion into patients, which do not necessarily contain a therapeuticagent. Unfortunately, many such medical devices are commonly associatedwith some degree of patient discomfort or pain after being positionedwithin the patient. As a specific example, EVA based ureteral stents arewidely used to facilitate drainage in the upper urinary tract (e.g.,from the kidney to the bladder), for example, following ureteroscopy,endourerotomies, and endopyelotomy for ureteral strictures, as well asin other instances where ureteral obstruction may occur. However, suchstents are typically associated with pain and discomfort in the bladderand flank area after insertion. At present, one way by which pain anddiscomfort are minimized is to orally administer drugs to the patient.To date the most commonly prescribed oral drugs are opioid analgesia,which are controlled substances and have the potential for abuse bypatients.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, implantable orinsertable medical devices are provided, which comprise: (a) abiocompatible polymer; and (b) at least one therapeutic agent selectedfrom an anti-inflammatory agent, an analgesic agent, an anestheticagent, and an antispasmodic agent. The medical devices are adapted forimplantation or insertion at sites associated with pain or discomfortupon implantation or insertion.

In many embodiments, the therapeutic agent will be selected from atleast one of (i) ketorolac and pharmaceutically acceptable salts thereof(e.g., ketorolac tromethamine) and (ii)4-diethylamino-2-butynylphenylcyclohexylglycolate and pharmaceuticallyacceptable salts thereof (e.g., oxybutynin chloride).

The medical device may also contain one or more optional agents,including one or more radio-opacifying agents such as bismuthsubcarbonate (e.g., to enhance visibility), and one or moreantimicrobial agents such as triclosan (e.g., to reduce microbialbuildup along the device).

The implantable or insertable medical devices of the present inventioncan be provided with a variety of release profiles. For instance, acumulative therapeutic agent release selected from 5%, 10%, 15%, 20%,25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, and 99%, relative to thetotal therapeutic agent in the device, can be obtained afterimplantation or insertion for a period selected from 1 day, 2 days, 4days, 1 week, 2 weeks, 1 month, 2 months, 4 months, 1 year and 2 years.

A variety of biocompatible polymers can be used in the medical devicesof the present invention. For example, biocompatible polymers can beselected from polyether block amides, thermoplastic polyurethanes,ethylene-vinyl acetates, and/or polyoctenamers, among others.

In accordance with many embodiments of the present invention, themedical devices will comprise one or more polymeric matrix regionscomprising the following: (a) one or more biocompatible polymers, (b)one or more therapeutic agents, (c) one or more optionalradio-opacifying agents, and/or (d) one or more optional antimicrobialagents.

For example, in one embodiment, the medical device comprises a polymericmatrix region comprising biocompatible polymer, therapeutic agent andradio-opacifying agent. In another embodiment, medical device comprises(a) a first polymeric matrix region comprising a first biocompatiblepolymer and a therapeutic agent, and (b) a second polymer matrix regioncomprising a second biocompatible polymer and a radio-opacifying agent;the first and second biocompatible polymers may be the same ordifferent.

In addition to one or more matrix regions, the medical devices caninclude various other regions, for example, hydrogel layers and/orbarrier layers.

Other aspects of the present invention are directed to uses for theimplantable or insertable medical devices disclosed herein. In general,these uses comprise reducing the pain or discomfort accompanying theimplantation or insertion of such devices. Further uses may comprise,for example, reducing microbial buildup along the device.

Still other aspects of the present invention concern methods formanufacturing the implantable or insertable medical devices disclosedherein.

According to various embodiments of the present invention, methods ofmanufacturing polymeric matrices are provided, which comprise: (a)providing a combination that comprises biocompatible polymer andtherapeutic agent; and (b) forming a polymeric matrix from thecombination.

In some embodiments, forming the polymeric matrix comprises athermoplastic process, such as an extrusion process. In general, it ispreferred for various processes of the present invention to be conductedunder conditions such that substantial degradation of the therapeuticagent is avoided. For example, where thermoplastic techniques areutilized, it may be useful to process the matrix at a temperature thatis (a) above the softening temperature of the biocompatible polymer, (b)below the melting point of the therapeutic agent, and (c) sufficientlylow to avoid substantial degradation of the therapeutic agent. It isalso desirable to control shear in many embodiments to avoid substantialdegradation of the therapeutic agent.

As a specific example, an extruded matrix comprising ethylene-vinylacetate (EVA) copolymer, ketorolac tromethamine and bismuth subcarbonatecan be formed under conditions of diminished temperature and shear, suchthat the degradation level of the ketorolac tromethamine is less than2%.

In other embodiments of the invention, forming the polymeric matrixcomprises a solution forming process, for example, a solution coatingprocess.

One advantage of the present invention is that implantable or insertablemedical devices can be provided, which are able to provide localizedrelief of pain and discomfort upon implantation or insertion.

Another advantage of the present invention is that thermally sensitivetherapeutic agents can be processed using thermoplastic processingtechniques, which heretofore would have resulted in unacceptabledegradation of therapeutic agent.

These and other embodiments and advantages of the present invention willbecome immediately apparent to those of ordinary skill in the art uponreview of the Detailed Description and claims to follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a simplified schematic representation of an annular medicaldevice for implantation or insertion into the body, according to anembodiment of the invention.

FIG. 2 is a simplified schematic representation of an annular medicaldevice for implantation or insertion into the body, according to anotherembodiment of the invention.

FIG. 3 is a simplified schematic representation of an annular medicaldevice for implantation or insertion into the body, according to yetanother embodiment of the invention.

FIG. 4 is a simplified schematic representation of an annular medicaldevice for implantation or insertion into the body, according to yetanother embodiment of the invention.

FIG. 5 is a plot of estimated daily dose of ketorolac based on releaseas a function of time at 37° C. in artificial urine, in accordance withan embodiment of the present invention.

FIG. 6 is a plot of estimated in vitro cumulative ketorolac releasebased on release as a function of time at 37° C. in artificial urine, inaccordance with an embodiment of the present invention.

FIG. 7 is a plot of ketorolac concentration as a function of time at 37°C. in artificial urine, in accordance with an embodiment of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention is directed to an implantable orinsertable medical device that comprises (a) a biocompatible polymer and(b) a therapeutic agent selected from an anti-inflammatory agent, ananalgesic agent, a local anesthetic agent, and an antispasmodic agent.The medical device is of a type such that symptoms of pain or discomfortare typically experienced by the patient (e.g., a mammalian subject suchas a human subject) after implantation or insertion.

Another aspect of the invention is directed to the use of such animplantable or insertable medical device to bring about a reduction indiscomfort or pain subsequent to implantation or insertion (in additionto other therapeutic benefits that the device is implanted/inserted toprovide, for example, to facilitate drainage, etc.). In someembodiments, the medical device will also be used to resist microbialgrowth and/or biofilm formation.

As a specific example, ureteral stents, for instance, ethylene-vinylacetate (EVA) based ureteral stents, are widely used in urology tofacilitate drainage in the upper urinary tract (e.g., from the kidney tothe bladder) following various procedures (e.g., ureteroscopy,endourerotomies, endopyelotomy for ureteral strictures, as well as inother instances where ureteral obstruction is encountered). However, asnoted above, such stents are typically associated with pain anddiscomfort after insertion. One way by which pain and discomfort areminimized is to orally administer drugs to the patient, which drugs aretypically opioid analgesia having the potential for abuse by patients.In addition, drugs administered locally with the intention of providinga site-specific effect require significantly lower doses than oraladministration of the same drug for the same therapeutic purpose. Theadvantage of the lower doses in site-specific delivery is that oftenunwanted or even toxic side affects of systemic concentrations of thesame drug can be avoided.

A different approach is taken in various embodiments of the invention,wherein the pain and discomfort associated with the presence ofimplantable or insertable medical devices is addressed locally, ratherthan systemically. In these embodiments, a therapeutic agent selectedfrom an anti-inflammatory agent, an analgesic agent, an anestheticagent, and an antispasmodic agent is disposed within the medical devicein a fashion such that the therapeutic agent is released into thepatient upon implantation or insertion of the device. Medical deviceshaving an extended release profile are preferred in many cases. By“extended release profile” is meant a release profile by which atherapeutically effective amount of therapeutic agent continues to bereleased for up to 1 day, 2 days, 4 days, 1 week, 2 weeks, 1 month, 2months, 6 months, 1 year or even 2 years, in some embodiments afterimplantation/insertion.

The medical devices for use in connection with the present invention maybe selected from essentially any implantable or insertable medicaldevice. Examples of implantable medical devices include stents, stentgrafts, stent covers, catheters, venous access devices, vena cavafilters, peritoneal access devices, injectables/bulking agents, sutures,surgical meshes, enteral feeding devices used in percutaneous endoscopicgastronomy, prosthetic joints, and artificial ligaments and tendons.

Catheters for the practice of the present invention include urinary andvascular catheters.

Stents for the practice of the present invention include biliary,urethral, ureteral, tracheal, coronary, gastrointestinal, and esophagealstents. The stents may be of any shape or configuration. The stents maycomprise a hollow tubular structure, which is particularly useful inproviding flow or drainage through ureteral or biliary lumens. Stentsmay also be coiled or patterned as a braided or woven open network offibers or filaments or, for example, as an interconnecting open networkof articulable segments. Thus, stents can have a continuous wallstructure or discontinuous open network wall structure.

Stent covers for the practice of the present invention may comprise atubular or sheath-like structure adapted to be placed over a stent,which can comprise, for example, an open mesh of knitted, woven orbraided design. The stent can be made of any material useful for suchpurpose including metallic and non-metallic materials as well as shapememory materials. Among useful metallic materials include, but are notlimited to, shape memory alloys such as nickel-titanium alloys and othermetallic materials including, but not limited to, stainless steel,tantalum, nickel-chrome, or cobalt-chromium, for example, Nitinol® andElgiloy®.

In many embodiments of the invention, a therapeutic agent of interest isreleased from a polymeric matrix. The term “polymeric matrix” refers toa region that comprises a biocompatible polymer and at least oneadditive, for example, one or more therapeutic agents, one or moreradio-opacifying agents, one or more pigments, and/or one or moreantimicrobial agents, among other materials. The polymeric matrix canconstitute the entirety of an implantable or insertable medical device,or it can correspond to only a portion or region of the medical device.

Where only a single distinct polymeric matrix region is provided in themedical device, the polymeric matrix region will preferably contain thetherapeutic agent as well as any optional additives, such asradio-opacifying agents, pigments, antimicrobial agents, plasticizers,lubricants, and so forth. In other embodiments, the medical devicecomprises two or more distinct polymeric matrix regions. Where two ormore distinct polymeric matrix regions are present in the medicaldevice, it is not necessary that the therapeutic agent and any optionaladditive(s) be present in a single polymeric matrix region. For example,a therapeutic agent may be present in a first polymeric matrix region,and one or more optional additives may be present in a second polymericmatrix region distinct from the first polymeric matrix region.

Without wishing to be bound by theory, it is believed that therapeuticagent is released from a non-biodegradable polymeric matrix region, atleast in part, by a mechanism wherein the polymeric matrix imbibes orcontacts physiological fluid. In such a polymeric matrix, thetherapeutic agent may diffuse to some extent through the polymer matrixtoward an external surface and/or the physiological fluid diffuses intothe polymeric matrix. The therapeutic agent then dissolves in thephysiological fluid. A concentration gradient is believed to be set upat or near the matrix region, and the therapeutic agent in solution isthen released via diffusion into the surrounding physiological fluid andlocal tissues. Where the polymeric matrix is biodegradable, similardiffusion-dissolution-diffusion processes may also occur. In abiodegradable polymeric matrix, however, therapeutic agent may also bereleased as the biodegradable polymeric matrix containing thetherapeutic agent biodegrades upon contact with the physiologicalenvironment where the device is implanted/inserted. Thus, in abiodegradable polymer, therapeutic agent may be released bydissolution/diffusional processes and upon biodegradation of the polymermatrix.

In general, the therapeutic agent for use in connection with the presentinvention can be any pharmaceutically acceptable therapeutic agent. Asused herein “pharmaceutically acceptable” means that an agent that isapproved or capable of being approved by the United States Food and DrugAdministration or Department of Agriculture for use in humans or animalswhen incorporated in or on an implantable or insertable medical device.As noted above, preferred therapeutic agents include anti-inflammatoryagents, analgesic agents, local anesthetic agents, antispasmodic agents,and combinations thereof.

Anti-inflammatory agents include steroidal and non-steroidalanti-inflammatory agents. Examples of non-steroidal anti-inflammatorydrugs include aminoarylcarboxylic acid derivatives such as enfenamicacid, etofenamate, flufenamic acid, isonixin, meclofenamic acid,mefanamic acid, niflumic acid, talniflumate, terofenamate and tolfenamicacid; arylacetic acid derivatives such as acemetacin, alclofenac,amfenac, bufexamac, cinmetacin, clopirac, diclofenac sodium, etodolac,felbinac, fenclofenac, fenclorac, fenclozic acid, fentiazac,glucametacin, ibufenac, indomethacin, isofezolac, isoxepac, lonazolac,metiazinic acid, oxametacine, proglumetacin, sulindac, tiaramide,tolmetin and zomepirac; arylbutyric acid derivatives such as bumadizon,butibufen, fenbufen and xenbucin; arylcarboxylic acids such as clidanac,ketorolac and tinoridine; arylpropionic acid derivatives such asalminoprofen, benoxaprofen, bucloxic acid, carprofen, fenoprofen,flunoxaprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen,ketoprofen, loxoprofen, miroprofen, naproxen, oxaprozin, piketoprofen,pirprofen, pranoprofen, protizinic acid, suprofen and tiaprofenic acid;pyrazoles such as difenamizole and epirizole; pyrazolones such asapazone, benzpiperylon, feprazone, mofebutazone, morazone,oxyphenbutazone, phenybutazone, pipebuzone, propyphenazone,ramifenazone, suxibuzone and thiazolinobutazone; salicylic acid and itsderivatives such as acetaminosalol, aspirin, benorylate, bromosaligenin,calcium acetylsalicylate, diflunisal, etersalate, fendosal, gentisicacid, glycol salicylate, imidazole salicylate, lysine acetylsalicylate,mesalamine, morpholine salicylate, 1-naphthyl salicylate, olsalazine,parsalmide, phenyl acetylsalicylate, phenyl salicylate, salacetamide,salicylamine o-acetic acid, salicylsulfuric acid, salsalate andsulfasalazine; thiazinecarboxamides such as droxicam, isoxicam,piroxicam and tenoxicam; others such as ε-acetamidocaproic acid,s-adenosylmethionine, 3-amino-4-hydroxybutyric acid, amixetrine,bendazac, benzydamine, bucolome, difenpiramide, ditazol, emorfazone,guaiazulene, nabumetone, nimesulide, orgotein, oxaceprol, paranyline,perisoxal, pifoxime, proquazone, proxazole and tenidap; andpharmaceutically acceptable salts thereof.

Examples of steroidal anti-inflammatory agents (glucocorticoids) include21-acetoxyprefienolone, aalclometasone, algestone, amicinonide,beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol,clobetasone, clocortolone, cloprednol, corticosterone, cortisone,cortivazol, deflazacort, desonide, desoximetasone, dexamethasone,diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort,flucloronide, flumehtasone, flunisolide, fluocinolone acetonide,fluocinonide, fluocortin butyl, fluocortolone, fluorometholone,fluperolone acetate, fluprednidene acetate, fluprednisolone,flurandrenolide, fluticasone propionate, formocortal, halcinonide,halobetasol priopionate, halometasone, halopredone acetate,hydrocortamate, hydrocortisone, loteprednol etabonate, mazipredone,medrysone, meprednisone, methyolprednisolone, mometasone furoate,paramethasone, prednicarbate, prednisolone, prednisolone25-diethylaminoacetate, prednisone sodium phosphate, prednisone,prednival, prednylidene, rimexolone, tixocortal, triamcinolone,triamcinolone acetonide, triamcinolone benetonide, triamcinolonehexacetonide, and pharmaceutically acceptable salts thereof.

Analgesic agents include narcotic and non-narcotic analgesics. Narcoticanalgesic agents include alfentanil, allylprodine, alphaprodine,anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol,clonitazene, codeine, codeine methyl bromide, codeine phosphate, codeinesulfate, desomorphine, dextromoramide, dezocine, diampromide,dihydrocodeine, dihydrocodeinone enol acetate, dihydromorphine,dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,dipipanone, eptazocine, ethoheptazine, ethylmethlythiambutene,ethylmorphine, etonitazene, fentanyl, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol, lofentanil,meperidine, meptazinol, metazocine, methadone hydrochloride, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenazocine, pheoperidine,piminodine, piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, rumifentanil, sufentanil, tilidine, and pharmaceuticallyacceptable salts thereof

Non-narcotic analgesics include aceclofenac, acetaminophen,acetaminosalol, acetanilide, acetylsalicylsalicylic acid, alclofenac,alminoprofen, aloxiprin, aluminum bis(acetylsalicylate),aminochlorthenoxazin, 2-amino-4-picoline, aminopropylon, aminopyrine,ammonium salicylate, amtolmetin guacil, antipyrine, antipyrinesalicylate, antrafenine, apazone, aspirin, benorylate, benoxaprofen,benzpiperylon, benzydamine, bermoprofen, brofenac, p-bromoacetanilide,5-bromosalicylic acid acetate, bucetin, bufexamac, bumadizon, butacetin,calcium acetylsalicylate, carbamazepine, carbiphene, carsalam,chloralantipyrine, chlorthenoxazin(e), choline salicylate, cinchophen,ciramadol, clometacin, cropropamide, crotethamide, dexoxadrol,difenamizole, diflunisal, dihydroxyaluminum acetylsalicylate,dipyrocetyl, dipyrone, emorfazone, enfenamic acid, epirizole,etersalate, ethenzamide, ethoxazene, etodolac, felbinac, fenoprofen,floctafenine, flufenamic acid, fluoresone, flupirtine, fluproquazone,flurbiprofen, fosfosal, gentisic acid, glafenine, ibufenac, imidazolesalicylate, indomethacin, indoprofen, isofezolac, isoladol, isonixin,ketoprofen, ketorolac, p-lactophenetide, lefetamine, loxoprofen, lysineacetylsalicylate, magnesium acetylsalicylate, methotrimeprazine,metofoline, miroprofen, morazone, morpholine salicylate, naproxen,nefopam, nifenazone, 5′ nitro-2′ propoxyacetanilide, parsalmide,perisoxal, phenacetin, phenazopyridine hydrochloride, phenocoll,phenopyrazone, phenyl acetylsalicylate, phenyl salicylate, phenyramidol,pipebuzone, piperylone, prodilidine, propacetamol, propyphenazone,proxazole, quinine salicylate, ramifenazone, rimazolium metilsulfate,salacetamide, salicin, salicylamide, salicylamide o-acetic acid,salicylsulfuric acid, salsalte, salverine, simetride, sodium salicylate,sulfamipyrine, suprofen, talniflumate, tenoxicam, terofenamate,tetradrine, tinoridine, tolfenamic acid, tolpronine, tramadol, viminol,xenbucin, zomepirac, and pharmaceutically acceptable salts thereof.

Local anesthetic agents include amucaine, amolanone, amylocainehydrochloride, benoxinate, benzocaine, betoxycaine, biphenamine,bupivacaine, butacaine, butaben, butanilicaine, butethamine,butoxycaine, carticaine, chloroprocaine hydrochloride, cocaethylene,cocaine, cyclomethycaine, dibucaine hydrochloride, dimethisoquin,dimethocaine, diperadon hydrochloride, dyclonine, ecgonidine, ecgonine,ethyl chloride, beta-eucaine, euprocin, fenalcomine, fomocaine,hexylcaine hydrochloride, hydroxytetracaine, isobutyl p-aminobenzoate,leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine,metabutoxycaine, methyl chloride, myrtecaine, naepaine, octacaine,orthocaine, oxethazaine, parethoxycaine, phenacaine hydrochloride,phenol, piperocaine, piridocaine, polidocanol, pramoxine, prilocaine,procaine, propanocaine, proparacaine, propipocaine, propoxycainehydrochloride, pseudococaine, pyrrocaine, ropavacaine, salicyl alcohol,tetracaine hydrochloride, tolycaine, trimecaine, zolamine, andpharmaceutically acceptable salts thereof.

Antispasmodic agents include alibendol, ambucetamide, aminopromazine,apoatropine, bevonium methyl sulfate, bietamiverine, butaverine,butropium bromide, n-butylscopolammonium bromide, caroverine,cimetropium bromide, cinnamedrine, clebopride, coniine hydrobromide,coniine hydrochloride, cyclonium iodide, difemerine, diisopromine,dioxaphetyl butyrate, diponium bromide, drofenine, emepronium bromide,ethaverine, feclemine, fenalamide, fenoverine, fenpiprane, fenpiveriniumbromide, fentonium bromide, flavoxate, flopropione, gluconic acid,guaiactamine, hydramitrazine, hymecromone, leiopyrrole, mebeverine,moxaverine, nafiverine, octamylamine, octaverine, oxybutynin chloride,pentapiperide, phenamacide hydrochloride, phloroglucinol, pinaveriumbromide, piperilate, pipoxolan hydrochloride, pramiverin, prifiniumbromide, properidine, propivane, propyromazine, prozapine, racefemine,rociverine, spasmolytol, stilonium iodide, sultroponium, tiemoniumiodide, tiquizium bromide, tiropramide, trepibutone, tricromyl,trifolium, trimebutine, n,n-1trimethyl-3,3-diphenyl-propylamine,tropenzile, trospium chloride, xenytropium bromide, and pharmaceuticallyacceptable salts thereof.

Two particularly preferred therapeutic agents for the practice of thepresent invention are (a) ketorolac and pharmaceutically acceptablesalts thereof (e.g., the tromethamine salt thereof, sold under thecommercial name Toradol®) and (b)4-diethylamino-2-butynylphenylcyclohexylglycolate and pharmaceuticallyacceptable salts thereof (e.g.,4-diethylamino-2-butynylphenylcyclohexylglycolate hydrochloride, alsoknown as oxybutynin chloride, sold under the commercial name Ditropan®).

The amount of the therapeutic agent present in the polymeric matrix isan amount effective to reduce the pain or discomfort associated with themedical device. Typically, the therapeutic agent is present in apolymeric matrix in a range from about 0.1% to about 40% by weight ofthe polymeric matrix (including 0.1%, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%,6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%,21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%,35%, 36%, 37%, 38%, 39%, 40%, and ranges between any two of thesepoints, for instance, 0.1-10%, 10-20% and 20-30%, etc.). Where theoxybutynin chloride and ketorolac tromethamine are used, a range of2-20% is typical, more typically 5-15%.

The amount of therapeutic agent present in a polymeric matrix willdepend upon, inter alia, the efficacy of the therapeutic agent employed,the length of time during which the medical device is to remainimplanted, as well as the rate at which the polymeric matrix or barrierlayer releases the therapeutic agent in the environment of the implantedmedical device. Thus, a device that is intended to remain implanted fora longer period will generally require a higher percentage of thetherapeutic agent. Similarly, a polymeric matrix that provides fasterrate of release of the therapeutic agent may require a higher percentageof the therapeutic agent. One skilled in the art can readily determinean appropriate therapeutic agent content to achieve the desired outcome.

The medical device of the present invention may also contain optionaladditives, including radio-opacifying agents, pigments, anti-microbialagents, and other additives such as plasticizers and extrusionlubricants, within its structure.

Thus, in some embodiments, the medical device further comprises aradio-opacifying agent, while in others it does not. For example, theradio-opacifying agent may be present in any polymeric matrix region ormay be uniformly distributed throughout the medical device.

The radio-opacifying agent facilitates viewing of the medical deviceduring insertion of the device and at any point while the device isimplanted. A radio-opacifying agent typically functions by scatteringx-rays. The areas of the medical device that scatter the x-rays aredetectable on a radiograph. Among radio-opacifying agents useful in themedical device of the present invention are included a bismuth salt suchas bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, bariumsulfate, tungsten, and mixtures thereof, with bismuth salts typicallybeing preferred. Where present, the radio-opacifying agent is typicallypresent in an amount of from about 10% to about 40% (including 10%, 11%,12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%,26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% and40%, as well as ranges between any two of these values, e.g., 10-15%,15-20%, 20-25%, 25-30%, 30-35%, 35-40%, and so forth, with 15-30% beingmore typical, even more typically 20-25%). One skilled in the art canreadily determine an appropriate radio-opacifying agent content toachieve the desired visibility.

Where bismuth subcarbonate is used as a radio-opacifying agent,increasing the bismuth subcarbonate content can result in either asofter or a stiffer material, dependent upon base material to which thebismuth subcarbonate is added.

In some embodiments of the present invention, the medical device furthercomprises an antimicrobial agent, while in others it does not. The term“antimicrobial agent” as used herein means a substance that kills and/orinhibits the proliferation and/or growth of microbes, particularlybacteria, fungi and yeast. Antimicrobial agents, therefore, includebiocidal agents and biostatic agents as well as agents that possess bothbiocidal and biostatic properties. In the context of the presentinvention, the antimicrobial agent kills and/or inhibits theproliferation and/or growth of microbes on and around the surfaces of animplanted medical device, and can therefore inhibit biofilm formation insome cases.

The antimicrobial agent can be any pharmaceutically acceptableantimicrobial agent. Preferred antimicrobial agents include triclosan,chlorhexidine, nitrofurazone, benzalkonium chlorides, silver salts andantibiotics such as rifampin, gentamycin and minocyclin and combinationsthereof. The antimicrobial agent can be included in an amount rangingfrom 1-30 wt % (including 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%,26%, 27%, 28%, 29%, 30%, and ranges between any two of these points, forinstance, 1-5%, 5-10%, 10-15%, 15-20%, etc.). As a specific example,where triclosan is used as an antimicrobial agent, it is typicallypresent in an amount ranging from 10-30%, more typically 5-15%.

Similar to the therapeutic agent, the amount of optional antimicrobialagent present in the structure will depend, inter alia, upon theefficacy of the agent employed, the length of time during which themedical device is intended to remain implanted, as well as the rate ofrelease into the environment of the implanted medical device. Thus, adevice that is intended to remain implanted for a longer period willgenerally require a higher percentage of the antimicrobial agent.Similarly, a faster release of the antimicrobial agent may require ahigher amount of the bioactive agent. One skilled in the art can readilydetermine an appropriate antimicrobial agent content to achieve thedesired outcome.

In this connection, it is noted that certain of the therapeutic agentslisted above are useful in providing microbial resistance. For example,non-steroidal anti-inflammatory drugs (NSAIDs), for example, salicylicacid, its salts and its derivatives, have been described as microbialattachment/biofilm synthesis inhibitors. A “microbial attachment/biofilmsynthesis inhibitor” is a substance that inhibits the attachment ofmicrobes onto a surface and/or the ability of such microbes tosynthesize or accumulate biofilm on a surface. Further information canbe found in the above-incorporated U.S. Ser. No. 10/071,840.

In some embodiments, the medical device further comprises a pigment,while in others it does not. Pigments include any biocompatible andpharmaceutically acceptable colorant, regardless of type or color,including titanium dioxide, phthalocyanine organic pigments, quinaridoneorganic pigments, carbon black, iron oxides, and ultramarines. Wherepresent, pigment is typically included in an amount ranging from 0.001to 5%, more typically from 0.01 to 1%.

The polymeric regions used in the implantable or insertable medicaldevice of the present invention may comprise any biocompatible polymersuitable for use in implantable or insertable medical devices. Thebiocompatible polymer may be substantially non-biodegradable orbiodegradable.

The term “biocompatible” as used herein describes a material that is notsubstantially toxic to the human body, and that does not significantlyinduce inflammation or other adverse response in body tissues.Biocompatible polymers include essentially any polymer that is approvedor capable of being approved by the United States Food and DrugAdministration or Department of Agriculture for use in humans or animalswhen incorporated in or on an implantable or insertable medical device.Substantially non-biodegradable biocompatible polymers includethermoplastic and elastomeric polymeric materials. Polyolefins such aspolyethylenes (e.g., metallocene catalyzed polyethylenes),polypropylenes, and polybutylenes, polyolefin copolymers, e.g.,ethylenic copolymers such as ethylene vinyl acetate (EVA) copolymers,ethylene-methacrylic acid copolymers and ethylene-acrylic acidcopolymers, where some of the acid groups can be neutralized with eitherzinc or sodium ions (commonly known as ionomers); vinyl aromaticpolymers such as polystyrene; vinyl aromatic copolymers such asstyrene-isobutylene copolymers and butadiene-styrene copolymers;polyacetals; chloropolymers such as polyvinyl chloride (PVC);fluoropolymers such as polytetrafluoroethylene (PTFE); polyesters suchas polyethyleneterephthalate (PET); polyester-ethers; polyamides such asnylon 6 and nylon 6,6; polyethers; polyamide ethers such as polyetherblock amides (PEBA); polyoctenamers; thermoplastic polyurethanes (TPU);elastomers such as elastomeric polyurethanes and polyurethane copolymers(including block and random copolymers that are polyether based,polyester based, polycarbonate based, aliphatic based, aromatic basedand mixtures thereof; examples of commercially available polyurethanecopolymers include Carbothane®, Tecoflex®, Tecothane®, Tecophilic®,Tecoplast®, Pellethane®, Chronothane® and Chronoflex®); silicones;polycarbonates; and mixtures and block, alternating, or randomcopolymers of any of the foregoing are non-limiting examples ofnon-biodegradable biocompatible polymers useful in the medical devicesof the present invention.

Among particularly preferred non-biodegradable polymers are polyetherblock amides (PEBA), polyoctenamers such as Vestenamerg from DegussaCorp., Parsippany, N.J., which is a mixture of cyclic and linearpolyoctenamers, polyolefins, ethylenic copolymers including ethylenevinyl acetate copolymers (EVA) and copolymers of ethylene with acrylicacid or methacrylic acid; thermoplastic polyurethanes (TPU) andpolyurethane copolymers; metallocene catalyzed polyethylene (mPE), mPEcopolymers, ionomers, and mixtures and copolymers thereof; and vinylaromatic polymers and copolymers. Among preferred vinyl aromaticcopolymers are included copolymers of polyisobutylene with polystyreneor polymethylstyrene, even more preferablypolystyrene-polyisobutylene-polystyrene triblock copolymers. Thesepolymers are described, for example, in U.S. Pat. Nos. 5,741,331,4,946,899 and U.S. Pat. Appln. No. 20020107330, each of which is herebyincorporated by reference in its entirety.

Ethylene vinyl acetate (EVA) is a particularly preferrednon-biodegradable biocompatible polymer. Examples include EVA polymershaving a vinyl acetate content of from about 5% to about 40% (including5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%,20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%,34%, 35%, 35%, 36%, 37%, 38%, 39%, 40%, and including ranges between anytwo of these points, e.g., 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, and soforth, with 10-30% being typical). Increasing the EVA content typicallyresults in a softer material, while decreasing the EVA content typicallyproduces a harder material.

Among preferred biodegradable polymers are included polylactic acid,polyglycolic acid and copolymers and mixtures thereof such aspoly(L-lactide) (PLLA), poly(D,L-lactide) (PLA); polyglycolic acid[polyglycolide (PGA)], poly(L-lactide-co-D,L-lactide) (PLLA/PLA),poly(L-lactide-co-glycolide) (PLLA/PGA), poly(D, L-lactide-co-glycolide)(PLA/PGA), poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),poly(D,L-lactide-co-caprolactone) (PLA/PCL),poly(glycolide-co-caprolactone) (PGA/PCL); polyethylene oxide (PEO),polydioxanone (PDS), polypropylene fumarate, poly(ethylglutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethylglutamate), poly(carbonate-ester)s, polycaprolactone (PCL),polycaprolactone co-butylacrylate, polyhydroxybutyrate (PHBT) andcopolymers of polyhydroxybutyrate, poly(phosphazene), poly(phosphateester), poly(amino acid) and poly(hydroxy butyrate), polydepsipeptides,maleic anhydride copolymers, polyphosphazenes, polyiminocarbonates,poly[(97.5% dimethyl-trimethylene carbonate)-co-(2.5% trimethylenecarbonate)], cyanoacrylate, polyethylene oxide,hydroxypropylmethylcellulose, polysaccharides such as hyaluronic acid,chitosan and regenerate cellulose, and proteins such as gelatin andcollagen, and mixtures and copolymers thereof, among others.

The medical devices of the present invention may comprise a multilayerstructure comprising two or more layers. For example, the medicaldevices can comprise one or more polymeric matrix regions as notedabove. Furthermore, the medical devices may comprise a combination oftwo or more types of biocompatible polymers to produce desired physicalproperties for the medical devices. The medical devices can alsocomprise one or more barrier regions as well.

Multilayer structures of the present invention need not comprise abarrier layer. For example, a medical device in accordance with thepresent invention may comprise a two-layer structure comprising a firstpolymeric matrix layer containing biocompatible polymer, therapeuticagent and radio-opacifying agent, and a second layer on an externalsurface of the first polymeric matrix layer that provides lubricity.Such a lubricious layer may be desirable, for example, to facilitateinsertion, implantation and/or removal of the medical device. Asimplified schematic representation of a device of this type is depictedin FIG. 1, in accordance with an embodiment of the present invention.Implantable or insertable medical device 100 comprises an annularpolymeric matrix region 102, which further comprises a biocompatiblepolymer (e.g., EVA), a therapeutic agent (e.g., ketorolac tromethamineor oxybutynin chloride) and a radio-opacifying agent (e.g., bismuthsubcarbonate). The device 100 also comprises a lubricious layer 104(e.g., a hydrogel layer) at least partially covering an exterior surfaceof the annular polymeric matrix region 102.

As another example, a medical device in accordance with the presentinvention may comprise a three-layer structure comprising a first layercomprising biocompatible polymer, radio-opacifying agent and therapeuticagent, a second layer on an external surface of the first layer thatacts as a barrier layer, and a third layer on an external surface of thesecond layer that provides lubricity. A simplified schematicrepresentation of a device of this type is depicted in FIG. 2, inaccordance with an embodiment of the present invention. Referring now toFIG. 2, implantable or insertable medical device 100 comprises anannular polymeric matrix region 102, which further comprises abiocompatible polymer (e.g., EVA), a therapeutic agent (e.g., ketorolactromethamine or oxybutynin chloride) and a radio-opacifying agent (e.g.,bismuth subcarbonate). The device 100 also comprises a polymeric barrierlayer 106 (e.g., an EVA barrier layer) at least partially covering anexterior surface of the annular polymeric matrix region 102. The device100 further comprises a lubricious layer 104 (e.g., a hydrogel layer) atleast partially covering an exterior surface of the polymeric barrierlayer 106.

As another example, a medical device in accordance with the presentinvention may comprise a three-layer structure comprising a first layercomprising biocompatible polymer and radio-opacifying agent, a secondlayer on an external surface of the first layer comprising biocompatiblepolymer and the therapeutic agent, and a third layer on an externalsurface of the second layer that provides lubricity. A simplifiedschematic representation of a device of this type is depicted in FIG. 3,in accordance with an embodiment of the present invention. Referring nowto FIG. 3, implantable or insertable medical device 100 comprises anannular radio-opaque region 108, which comprises a biocompatible polymer(e.g., EVA) and a radio-opacifying agent (e.g., bismuth subcarbonate).Over the radio-opaque region 108 lies an annular polymeric matrix region102, which further comprises a biocompatible polymer (e.g., EVA) and atherapeutic agent (e.g., ketorolac tromethamine or oxybutynin chloride).The device 100 also comprises a lubricious layer 104 (e.g., a hydrogellayer) at least partially covering an exterior surface of the annularpolymeric matrix region 102.

As another example, a medical device in accordance with the presentinvention may comprise a structure comprising (a) a first regioncomprising a first therapeutic agent and a first biocompatible polymer,and (b) a second region comprising a second therapeutic agent and asecond biocompatible polymer. The regions may differ, for example, (a)because the first therapeutic agent differs from the second therapeuticagent, (b) because the first biocompatible polymer differs from thesecond biocompatible, or (c) because the first therapeutic agent differsfrom the second therapeutic agent and because the first biocompatiblepolymer differs from the second biocompatible polymer. A simplifiedschematic representation of a device of this type is depicted in FIG. 4,in accordance with an embodiment of the present invention. Referring nowto FIG. 4, implantable or insertable medical device 100 comprises afirst annular polymeric matrix section 102 a, which comprises arelatively soft matrix region, a therapeutic agent, and aradio-opacifying agent. The medical device 100 further comprises asecond annular polymeric matrix section 102 b, which comprises arelatively hard matrix region, a therapeutic agent, and aradio-opacifying agent. A medical device of this type may be formedusing a variety of extrusion techniques, including, for example,interrupted layer co-extrusion (ILC). See, for example, extrusionprocesses described in U.S. Pat. Nos. 5,622,665 and 6,508,805, which arehereby incorporated by reference. By virtue of the LC process, therelatively soft (low durometer) polymer section 102 a will transition tothe relatively hard (high durometer) polymer section 102 b. Thetransition between these regions is schematically illustrated by adashed line in FIG. 4.

It should be clear from the above that myriad possibilities existregarding the regions that can comprise the medical devices of thepresent invention, for example, the type of regions (e.g., matrixregions, barrier regions, lubricious regions, etc.), the number of theseregions, the shape of these regions, the distribution of these regionswithin the device, the composition of these regions, and so forth. Asspecific examples, (a) multiple regions (e.g., layers, sections, etc.)can be provided in one portion of the device, but not another, (b)different polymers can be provided in different regions of the device(e.g., different polymers in different layers along the radius of thedevice, or different polymers in different sections along the length ofthe stent), (c) different therapeutic agents can be provided indifferent regions of the device (e.g., different therapeutic agents indifferent layers along the radius of the device, or differenttherapeutic agents in different sections along the length of the stent),(d) different therapeutic agent concentrations can be provided indifferent regions of the device (e.g., different therapeutic agentconcentrations in along the radius of the device, or differenttherapeutic agent concentrations along the length of the stent), and soforth.

Medical devices in accordance with the present invention having multiplelayer structures may provide certain advantages relative to single layerdevices. For example, a barrier layer can be provided to control therate of release of therapeutic agent from an adjacent layer. It isunderstood, however, that the medical device of the present invention isnot limited to a multiple region structure and, indeed, a single regionstructure, for example, an annular tube comprising biocompatiblepolymer, therapeutic agent, and optional radio-opacifying agent iswithin the scope of the present invention.

The release characteristics of a particular therapeutic agent (or aparticular optional antimicrobial agent) commonly depend on the abilityof the therapeutic agent (or optional antimicrobial agent) to diffusefrom a particular polymeric matrix. Polymer matrices of differentcompositions typically exhibit different release characteristic. In thisconnection, release characteristics may be changed by changing, forexample, (1) the amount and type of biocompatible polymer, (2) theamount and type of therapeutic agent (or optional antimicrobial agent),and (3) the amount and type of any additional additives includingradio-opacifying agents, pigments, and so forth. Some compositions mayresult in relatively fast release while others may result in a slowerrelease profile. By appropriate selection of the materials comprisingthe polymeric matrix, as well as their respective amounts, the releaseprofile of the therapeutic agent (or optional antimicrobial agent) fromthe device may be optimized for a particular application.

Where used, lubricious layers preferably comprise one or more hydrogels.Hydrogels are typically hydrophilic polymeric materials that have theability to absorb large amounts, up to many times the weight of thehydrogel itself, of water or other polar molecules. Hydrogels have beendisclosed as coatings for implantable or insertable medical devices oras materials for constructing the device itself in, for example, U.S.Pat. Nos. 6,316,522; 6,261,630; 6,184,266; 6,176,849; 6,096,108;6,060,534; 5,702,754; 5,693,034; and, 5,304,121, each of which isincorporated by reference and assigned to Boston Scientific Corporationor SciMed Life Systems, Inc. Hydrogels can be based on synthetic ornaturally occurring materials or a composite thereof; can bebiodegradable or substantially non-biodegradable; and, can be modifiedor derivatized in numerous ways to render the hydrogel more suitable fora desired purpose. For example, a hydrogel can be modified by chemicallycross-linking with, for example, a polyfunctional cross-linking agentthat is reactive with functional groups covalently bonded to the polymerstructure. A hydrogel can also be ionically cross-linked with, forexample, polyvalent metal ions. Hydrogels can also be both chemicallyand ionically cross-linked. Examples of hydrogel polymers includepolyacrylates; poly(acrylic acids); poly(methacrylic acids);polyacrylamides; poly(N-alkylacrylamides); polyalkylene oxides;poly(ethylene oxide); poly(propylene) oxide; poly(vinyl alcohol);polyvinyl aromatics; poly(vinylpyrrolidone); poly(ethyleneimine);polyethylene amine; polyacrylonitrile; polyvinyl sulfonic acid;polyamides; poly(L-lysine); hydrophilic polyurethanes; maleic anhydridepolymers; proteins; collagen; cellulosic polymers; methyl cellulose;carboxymethyl cellulose; dextran; carboxymethyl dextran; modifieddextran; alginates; alginic acid; pectinic acid; hyaluronic acid;chitin; pullulan; gelatin; gellan; xanthan; carboxymethyl starch;chondroitin sulfate; guar; starch; and copolymers, mixtures andderivatives thereof. Suitable hydrophilic coatings include polyacrylicacid polymers available, for example, from Boston Scientific Corp.,Natick, Mass., under the trade designation HydroPlus™ and described inU.S. Pat. No. 5,091,205, the disclosure of which is hereby incorporatedherein by reference. Another suitable hydrogel is HydroPass™ alsoavailable from Boston Scientific Corp., Natick, Mass.

Where used, barrier layers preferably comprise polymeric materials. Anyof the non-biodegradable and biodegradable polymers describedhereinabove in relation to the polymeric matrix may also form a barrierlayer. Preferred barrier layer polymers include EVA, PEBA, TPU,polyoctenamers and mixtures thereof.

A barrier layer and any underlying polymeric matrix region may comprisethe same or different polymeric materials. Different polymeric materialswill generally provide different rates of diffusion or release oftherapeutic agent. Thus, less permeable barrier layers may be providedto control the rate of release of a therapeutic agent from an underlyingpolymeric matrix region, which may be more permeable to diffusion of atherapeutic agent. For example, where an EVA copolymer is used as thepolymeric matrix, another EVA copolymer having a higher vinyl acetatecontent may be useful to form the barrier layer. Higher vinyl acetatecontent EVA copolymers are useful as barrier layers due to their lowerpermeability to certain therapeutic agents, and hence their ability torelease therapeutic agent more slowly than lower vinyl acetate contentcopolymers. The relative rigidity or stiffness of such higher vinylacetate content barrier layers may be offset somewhat by the use oflower vinyl acetate content in the underlying polymeric matrix region,by the addition of additives that may increase softness, such as bismuthsubcarbonate, to the underlying polymeric matrix region, and so forth.

Further, where a barrier (or other) layer is provided any of the abovesupplemental additives, for example radio-opacifying agent,anti-microbial agent, pigment, etc. may be provided in a barrier orother layer.

Thus, a medical device in accordance with the present invention, forexample, can be constructed of single/multiple layers/regions, can haveone or multiple polymeric matrix regions, can have none, one or multiplebarrier regions, and can have none, one or more lubricious regions, orother regions. Moreover, neither the polymeric matrix nor the barrierregion nor the lubricous region need be annular as depicted in theFigures.

In accordance with another aspect of the present invention, methods ofmanufacturing an implantable or insertable medical device are provided,which comprise: (a) providing one or more biocompatible polymers, one ormore therapeutic agents and, optionally, one or more radio-opacifyingagents and/or anti-microbial agents; (b) forming at least a portion ofthe medical device by processing the one or more biocompatiblepolymer(s), therapeutic agent(s), and optional materials.

In this connection, it is noted that many therapeutic agents, includingoxybutynin chloride and ketorolac tromethamine discussed above, areprone to substantial degradation under conditions of elevatedtemperature and/or mechanical shear. By “substantial degradation” ismeant that more than 10% by weight of the therapeutic agent (based onthe initial weight of the therapeutic agent) is degraded duringprocessing. Accordingly, various embodiments of the present inventionare directed to processing conditions that avoid substantial degradationof therapeutic agent. Preferably, less than 7%, 5%, 3%, or 2%, and morepreferably less than 1% of any therapeutic agent is degraded duringprocessing in accordance with the present invention.

Various techniques are available for forming at least a portion of amedical device from the biocompatible polymer(s), therapeutic agent(s),and optional materials, including solution processing techniques andthermoplastic processing techniques.

Where solution processing techniques are used, a solvent system istypically selected that contains one or more solvent species. Thesolvent system is generally a good solvent for at least one component ofinterest, for example, biocompatible polymer and/or therapeutic agent.The particular solvent species that make up the solvent system can alsobe selected based on other characteristics, including drying rate andsurface tension.

Preferred solution processing techniques include solvent castingtechniques, spin coating techniques, web coating techniques, solventspraying techniques, dipping techniques, techniques involving coatingvia mechanical suspension, including air suspension (e.g., fluidizedcoating), ink jet techniques and electrostatic techniques. Whereappropriate, techniques such as those listed above can be repeated orcombined to build up a release region to a desired thickness.

In many embodiments, a solution containing solvent and biocompatiblepolymer is applied to a medical device substrate, or to another templatesuch as a mold, to form a device or device portion of interest. In thisway, polymeric regions, including barrier layers, lubricious layers, andso forth can be formed. If desired, the solution can further comprise,one or more of the following: therapeutic agent(s) and other optionaladditives such as radio-opacifying agent(s), pigment(s), anti-microbialagent(s), etc. in dissolved or dispersed form. This results in apolymeric matrix region containing these species after solvent removal.

In other embodiments, a solution containing solvent with dissolved ordispersed therapeutic agent is applied to a pre-existing polymericregion, which can be formed using a variety of techniques includingsolution processing and thermoplastic processing techniques, whereuponthe therapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the devices or deviceportions of the present invention include molding techniques (forexample, injection molding, rotational molding, and so forth), extrusiontechniques (for example, extrusion, co-extrusion, multi-layer extrusion,multi-lumen extrusion, and so forth) and casting.

Thermoplastic processing in accordance with the present inventiontypically comprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: therapeuticagent(s), radio-opacifying agent(s), pigment(s), anti-microbialagent(s), and so forth. The resulting mixture is then shaped into animplantable or insertable medical device or a portion thereof. Themixing and shaping operations, as described more fully below, may beperformed using any of the conventional devices known in the art forsuch purposes. In the description, therapeutic agent(s),radio-opacifying agent(s), anti-microbial agent(s), pigment(s), and soforth will, at times, be referred to as “additives” or “agents.”

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, oxybutynin chloride and ketorolac tromethamine,two therapeutic agents that are particularly preferred for the practiceof the present invention, are prone to substantial degradation underordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10%. More typicallydegradation is held to less than 7%, 5%, 3%, 2%, or preferably less than1%. Among the processing conditions that may be controlled duringprocessing to avoid substantial degradation of the therapeutic agent(s)are temperature, applied shear rate, applied shear stress, residencetime of the mixture containing the therapeutic agent, and the techniqueby which the polymeric material and the therapeutic agent are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives to form a mixture. A common way of doing so is to applymechanical shear to a mixture of the biocompatible polymer(s) andadditive(s). Devices in which the biocompatible polymer(s) andadditive(s) may be mixed in this fashion include devices such as singlescrew extruders, twin screw extruders, banbury mixers, high-speedmixers, ross kettles, and so forth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in a preferred embodiment, biocompatible polymer isprecompounded with radio-opacifying agent under conditions oftemperature and mechanical shear that would result in substantialdegradation of the therapeutic agent, if it were present. Thisprecompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the medical device or device component ofinterest.

Conversely, in another embodiments, biocompatible polymer can beprecompounded with therapeutic agent under conditions of reducedtemperature and mechanical shear. This precompounded material is thenmixed with radio-opacifying agent, also under conditions of reducedtemperature and mechanical shear, and the resulting mixture is shapedinto the medical device or device component of interest.

It has been noted by the inventors, that the presence of certainadditives, for example, radio-opacifying agents such as bismuthsubcarbonate, during thermoplastic processing results in substantiallyhigher degradation of therapeutic agent than would otherwise occur underconditions of similar mechanical shear and temperature in the absence ofthese additives. Without wishing to be bound by theory, it is believedthat the presence of these additives, which remain in solid form undertypical thermoplastic processing conditions, create localized regions ofheightened shear and/or temperature, increasing therapeutic agentdegradation. However, when such additives are precompounded with thebiocompatible polymer prior to addition of the therapeutic agent, orwhen therapeutic agent is precompounded with the biocompatible polymerprior to addition of such additives, the level of degradation can besubstantially decreased. Once the therapeutic agent is added, furtherthermoplastic processing is typically conducted under temperature andmechanical shear conditions, which are as low as possible.

The conditions used to achieve a mixture of the biocompatible polymerand additives will depend on a number of factors including, for example,the specific biocompatible polymer(s) and additive(s) used, as well asthe type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where apolymeric matrix region is formed comprising EVA polymer, aradio-opacifying agent (e.g., bismuth subcarbonate), and a therapeuticagent prone to degradation by heat and/or mechanical shear (e.g.,ketorolac tromethamine and/or oxybutynin chloride), it is preferred topremix the EVA with the radio-opacifying agent at temperatures of about170-180° C., which are common processing conditions for EVA polymers. Atwin screw extruder is preferred for this purpose, but other apparatuscan be used. The therapeutic agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for EVA compositions. For example, where extrudersare used, barrel temperature, volumetric output are typically controlledto limit the shear and therefore to prevent substantial degradation ofthe therapeutic agent(s). For instance, the therapeutic agent andpremixed composition can be mixed/compounded using a twin screw extruderat substantially lower temperatures (e.g., 100-105° C.), and usingsubstantially reduced volumetric output (e.g., less than 30% of fullcapacity, which generally corresponds to a volumetric output of lessthan 200 cc/min). It is noted that this processing temperature is wellbelow the melting points of ketorolac tromethamine and oxybutyninchloride, because processing at or above these temperatures will resultin substantial therapeutic agent degradation. It is further noted thatin certain embodiments, the processing temperature will be below themelting point of all bioactive compounds within the composition,including the therapeutic agent and any antibacterial agent that ispresent. After compounding, the resulting product is shaped into thedesired form, also under conditions of reduced temperature and shear.For example, a single screw extruder can be used for this purpose,operated at substantially reduced temperatures (e.g., 105-110° C.) usingsubstantially reduced volumetric output (e.g., less than 40% of fullcapacity, which generally corresponds to a volumetric output of lessthan 100 cc/min).

It is noted that some combinations of biocompatible polymer(s) andadditive(s) can be processed at temperatures that are lower thanotherwise might be expected. For example, 100-110° C. is a relativelylow temperature for processing an EVA copolymer, a radio-opacifyingagent such as bismuth subcarbonate, and a therapeutic agent such asketorolac tromethamine or oxybutynin chloride. However, by adding anantimicrobial agent such as triclosan, which melts at a temperature ofaround 55° C., the triclosan can act as a plasticizer for the EVA,facilitating use of lower temperatures, for example, about 80° C. toabout 90° C.

In other embodiments, biodegradable polymer(s) and one or more additivesare premixed using non-thermoplastic techniques. For example, thebiocompatible polymer can be dissolved in a solvent system containingone or more solvent species. Any desired agents (for example,radio-opacifying agent, therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, therapeutic agent can be dissolved or dispersed in asolvent system, which is then applied to a pre-existing polymeric region(the pre-existing polymeric region can be formed using a variety oftechniques including solution and thermoplastic processing techniques,and it can comprise a variety of additives including radio-opacifyingagent and/or pigment), whereupon the therapeutic agent is imbibed intothe polymeric region. As above, the resulting solid material can then begranulated for further processing, if desired.

Extrusion processes are a preferred group of thermoplastic processes forthe practice of the present invention. For example, as indicated above,a medical device or device portion can be formed by extruding a singleannular polymeric matrix containing biocompatible polymer(s),therapeutic agent(s) and radio-opacifying agent(s).

Co-extrusion is a shaping process that can be used to produce amulti-region structure (for example, a structure comprising one or morepolymeric matrix regions, and one or more barrier layers, each at leastpartially covering a surface of a polymeric matrix region). Multi-regionstructures can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

Where multiple regions are provided, various processes, including any ofthose discussed above, can also be used in various combinations. Forexample, a barrier layer can be extruded onto a preformed polymericmatrix region using an extrusion coating process. This process isdistinguished from a co-extrusion process in which the polymeric matrixand barrier layers are shaped substantially simultaneously. As anotherexample, a barrier layer can be applied to a surface of a preformedpolymeric matrix by applying a solution or dispersion of a barrierpolymer onto a surface of a preformed polymeric matrix region followedby removing the solvent or liquid dispersing agent, e.g., byevaporation. Such a solution or dispersion of the barrier polymer may beapplied by contacting a surface of the preformed polymeric matrix usingany of the techniques discussed above, for example, dipping or spraying.Of course, the use of these additional shaping processes is not limitedto the application of a barrier layer to a polymeric matrix region. Forexample, an additional polymeric matrix region or a lubricious coatingmay also be formed by similar methods, among other regions.

In many embodiments of the present invention, including variousextrusion embodiments, the product that emerges from the thermoplasticprocessing device (e.g., an annulus, or tube, that emerges from anextruder) is cooled. Examples of cooling processes include air coolingand/or immersion in a cooling bath. In some preferred embodiments, awater bath is used to cool the extruded product. However, where awater-soluble therapeutic agent such as ketorolac tromethamine oroxybutynin chloride is used, the immersion time should be held to aminimum to avoid unnecessary loss of therapeutic agent into the bath.Immediate removal of water or moisture by use of ambient or warm airjets after exiting the bath will also prevent re-crystallization of thedrug on the device surface, thus controlling or minimizing a high drugdose dump upon implantation or insertion.

Once a medical device is formed, it is typically packaged andsterilized. Implantable or insertable medical devices are commonlysterilized by exposure to ethylene oxide or to radiation. As in deviceformation, care should be taken during device sterilization to avoidunnecessary degradation of the therapeutic agent and prolonged exposureto moisture.

For example, where the medical device contains ketorolac tromethamine,ethylene oxide sterilization has been found to be less desirable,because this process involves exposing the therapeutic agent to heat,moisture and reactive chemicals. On the other hand, it is also notedthat radiation sterilization can lead to degradation of the therapeuticagent. However, degradation can nonetheless be held to acceptablelevels, for example, (a) by using a relatively low energy radiation, forinstance, electron beam radiation, and (b) by minimizing exposure of themedical device to moisture, oxygen and light.

In one preferred embodiment, the medical device is placed in a foilpouch, which is either evacuated or is provided with an inert atmosphere(e.g., an atmosphere of nitrogen and/or noble gases such as argon,etc.), and the pouch is subsequently exposed to electron beam radiation.

The invention will be further described with reference to the followingnon-limiting Example. It will be apparent to those skilled in the artthat many changes can be made in the embodiments described in suchExample, consistent with the foregoing description, without departingfrom the scope of the present invention.

EXAMPLE

A single-layer matrix polymer structure is formed from a mixturecontaining 65.75 wt % and 52.75 wt % respectively of Elvax® 460, anethylene vinyl acetate copolymer having a 18 wt % vinyl acetate contentavailable from DuPont, (b) 26 wt % of bismuth subcarbonate as aradio-opacifying agent, (c) 8 wt % and 21 wt %, respectively, ofketorolac tromethamine, available from Spectrum Chemicals & LaboratoryProducts, as a non-steroidal anti-inflammatory drug, and (d) 0.25% bluepigment.

The bismuth subcarbonate, EVA copolymer, and blue color areprecompounded at 350° (177° C.), for example, in a Haake twin screwextruder.

Ketorolac is then mixed with the pre-compounded resin, and the resultingmixture is compounded at 215° F. (102° C.) using a Haake twin screwextruder at a reduced shear rate (<30% of full screw power). About 6-8inches of the length of extruded rod (instead of 6-8 feet of extrudedlength, which is more typical) is guided through a chilled water bath,followed by air drying. The total amount of degradation product in thecompounded resin is less than 0.3% (w/w, against the total amount ofdrug loaded).

The compounded resin is then extruded into 6 Fr. tubes using a DavisStandard 1″ single screw extruder at 225° F. Shear rate is controlled bykeeping the screw rate under 16 rpm. The take-off rate is about 18feet/min. As above, the extruded tube is subjected to a brief watercooling step, followed by air cooling. The total amount of degradationcaused by this extrusion step is less than or equal to 0.2%.

A flow through model is used to simulate human body conditions todetermine the release profile of ketorolac tromethamine. 50 cm lengthtubular samples of the above, which contain 8% and 21% ketorolactromethamine, respectively, were loaded into the model. The followingconditions were used: (a) release medium: artificial urine (normal pH˜6.5), which contains the components listed in Table 1 below, (b) flowrate: 0.50 mL/min, (c) temperature: 37° C., and (d) sample size: N=3.

Fluid samples are collected throughout the study and measured using HPLCto determine concentration of the therapeutic agent. The results areillustrated in FIGS. 5, 6 and 7, which present daily dose, cumulativerelease, and concentration, respectively, as a function of time.

TABLE 1 Component Grams Wt % Molarity Molarity mmol/L mg/dL Urea 19.41.94 3.33E−01 Urea 3.33E−01 333.3 2000 NaCl 8 0.80 1.41E−01 Na 1.77E−01176.8 406.6 MgSO₄*7H₂O 1.1 0.11 4.61E−03 Cl 1.45E−01 145.1 522.5 Na₂SO41.5 0.15 1.09E−02 SO4 1.55E−02 15.5 148.9 KH₂PO4 0.91 0.09 6.85E−03 PO41.37E−02 13.7 130.0 Na₂HPO4 0.94 0.09 6.83E−03 Ca 1.90E−03 1.9 7.6CaCl₂*2H₂O 0.27 0.03 1.90E−03 Mg 4.61E−03 4.6 11.2 DI Water 969.25 96.795.56E+01 K 6.85E−03 6.9 26.7

Further aspects and embodiments of the invention will now be described.In one aspect, an implantable or insertable medical device is providedwhich comprises: (a) a biocompatible polymer; and (b) at least onetherapeutic agent selected from an anti-inflammatory agent, an analgesicagent, an anesthetic agent, and an antispasmodic agent, wherein themedical device is adapted for implantation or insertion at a siteassociated with pain or discomfort upon implantation or insertion.

In certain embodiments, the medical device does not contain anantimicrobial agent.

In certain embodiments, the medical device further comprises aradio-opacifying agent.

In certain embodiments, the medical device is a ureteral stent.

Another aspect of the invention provides for the use of an implantableor insertable medical device. The use comprises reducing pain ordiscomfort accompanying implantation or insertion of the implantable orinsertable medical device, which comprises, (a) a biocompatible polymer;and (b) at lease one therapeutic agent selected from ananti-inflammatory agent, an analgesic agent, an anesthetic agent, and anantispasmodic agent, and a radio-opacifying agent.

In certain embodiments, the implantable or insertable medical devicefurther comprises a radio-opacifying agent.

In certain embodiments, the medical device is a ureteral stent.

In certain embodiments, the use of the device further comprises reducingmicrobial buildup along the device, wherein the device further comprisesan antimicrobial agent.

In accordance with another aspect, an implantable or insertable medicaldevice is provided that comprises: (a) a biocompatible polymer; and (b)at least one therapeutic agent selected from (i) ketorolac andpharmaceutically acceptable salts thereof and (ii)4-diethylamino-2-butynylphenylcyclohexylglycolate and pharmaceuticallyacceptable salts thereof, wherein the medical device is adapted forimplantation or insertion at a site that is associated with pain ordiscomfort upon implantation or insertion.

In certain embodiments, the therapeutic agent is ketorolac tromethamine.

In certain embodiments, the therapeutic agent is oxybutynin chloride.

In certain embodiments, the cumulative release of therapeutic agent isin an amount selected from 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, and 99%, relative to the total therapeutic agent inthe device, after implantation or insertion at the site for a periodselected from 1 day, 2 days, 4 days, 1 week, 2 weeks, 1 month 2 months,4 months, 1 year and 2 years.

In certain embodiments, the medical device is a ureteral scent.

In certain embodiments, the biocompatible polymer is selected from ormore of polyether block amides (PEBA), thermoplastic polyurethanes(TPU), and polyoctenamers.

In certain embodiments, the biocompatible polymer is an ethylene-vinylacetate (EVA) copolymer.

In certain embodiments, the medical device comprises a polymeric matrixregion comprising the biocompatible polymer and the therapeutic agent.

In certain embodiments, the medical device further comprises aradio-opacifying agent.

In certain embodiments, the medical device comprises a polymeric matrixregion comprising a biocompatible polymer, a therapeutic agent and aradio-opacifying agent.

In certain embodiments, the radio-opacifying agent is bismuthsubcarbonate.

In certain embodiments, the medical device comprises (a) a firstpolymeric matrix region comprising a first biocompatible polymer and atherapeutic agent, and (b) a second polymer matrix region comprising asecond biocompatible polymer and a radio-opacifying agent, wherein thefirst and second biocompatible polymers may be the same or different.

In certain embodiments, the matrix region comprises 5-20% therapeuticagent.

In certain embodiments, the therapeutic agent is ketorolac tromethamine.

In certain embodiments, the therapeutic agent is oxybutynin chloride.

In certain embodiments, the matrix region comprises 15-30%radio-opacifying agent.

In certain embodiments, the biocompatible polymer is a thermoplasticpolymer.

In certain embodiments, the thermoplastic polymer is an ethylene-vinylacetate (EVA) copolymer.

In certain embodiments, the biocompatible polymer is an elastomericpolymer.

In certain embodiments, the medical device further comprises a barrierlayer.

In certain embodiments, the device further comprises an antimicrobialagent.

In certain embodiments, the implantable or insertable medical devicecomprises a polymeric matrix region comprising a biocompatible polymer,a therapeutic agent and a radio-opacifying agent and further comprisesan antimicrobial agent.

In certain embodiments, the implantable or insertable medical devicefurther comprises a hydrogel.

In certain embodiments, the matrix is an extruded matrix.

In certain embodiments, the extruded matrix comprises ethylene-vinylacetate (EVA) copolymer, ketorolac tromethamine and bismuthsubcarbonate.

In certain embodiments, the degradation level of the ketorotactromethamine is less than 2%.

In accordance with another aspect of the invention, a method ofmanufacturing an implantable or insertable medical device like thatabove is provided which comprises: providing a combination comprisingthe biocompatible polymer and the therapeutic agent; and forming thepolymeric matrix from the combination.

In certain embodiments, forming the polymeric matrix comprises athermoplastic process.

In certain embodiments, the thermoplastic process is an extrusionprocess.

In certain embodiments, the thermoplastic process is conducted at atemperature that is (a) above the softening temperature of thebiocompatible polymer, (b) below the melting point of the therapeuticagent, and (c) sufficiently low to avoid substantial degradation of saidtherapeutic agent.

In certain embodiments, the mechanical shear is further controlled toavoid such substantial degradation.

In certain embodiments, forming the polymeric matrix comprises asolution forming process.

In certain embodiments, the solution forming process is a solutioncoating process.

In certain embodiments, the combination further comprises aradio-opacifying agent.

In certain embodiments, forming the polymeric matrix comprises (a)forming an initial blend comprising the biocompatible polymer and theradio-opacifying agent; (b) combining the initial blend and thetherapeutic agent; and (c) forming the polymeric matrix.

In certain embodiments, the initial blend is formed using athermoplastic process.

In certain embodiments, the initial blend is formed using an extrusionprocess.

In certain embodiments, the polymeric matrix is formed using a furtherthermoplastic process.

In certain embodiments, such a further thermoplastic process isconducted under conditions such that substantial degradation of thetherapeutic agent is avoided.

In certain embodiments, such a further thermoplastic process isconducted under conditions such that degradation of the therapeuticagent is less than 2%.

In certain embodiments, the initial blend is formed using a solutionprocess and the polymeric matrix is formed using a thermoplasticprocess.

What is claimed is:
 1. An implantable or insertable medical devicecomprising: a single-layer matrix polymer structure formed from amixture comprising an extruded polymeric matrix region comprising (a) abiocompatible polymer, (b) a radio-opacifying agent, and (c) at leastone therapeutic agent, wherein said medical device is adapted forimplantation or insertion at a site that is associated with pain ordiscomfort upon implantation or insertion, wherein said radio-opacifyingagent is bismuth subcarbonate, wherein said therapeutic agent isketorolac and pharmaceutically acceptable salts thereof, and whereinsaid biocompatible polymer is an ethylene-vinyl acetate (EVA) copolymer.2. The implantable or insertable medical device of claim 1, wherein saidmedical device comprises (a) a first extruded polymeric matrix regioncomprising a first biocompatible polymer and said therapeutic agent, and(b) a second extruded polymer matrix region comprising a secondbiocompatible polymer and said radio-opacifying agent, wherein saidfirst and second biocompatible polymers may be the same or different. 3.The implantable or insertable medical device of claim 1, wherein saidextruded polymeric matrix region comprises 5-20% therapeutic agent. 4.The implantable or insertable medical device of claim 1, wherein saidtherapeutic agent is ketorolac tromethamine.
 5. The implantable orinsertable medical device of claim 1, wherein said extruded polymericmatrix region comprises 15-30% radio-opacifying agent.
 6. Theimplantable or insertable medical device of claim 1, further comprisinga barrier layer.
 7. The implantable or insertable medical device ofclaim 1, further comprising an antimicrobial agent.
 8. The implantableor insertable medical device of claim 1, further comprising a hydrogel.9. The implantable or insertable medical device of claim 1, wherein theextruded polymeric matrix region comprises ethylene-vinyl acetate (EVA)copolymer, ketorolac tromethamine and bismuth subcarbonate.
 10. Theimplantable or insertable medical device of claim 9, wherein thedegradation level of the ketorolac tromethamine is less than 2%.
 11. Amethod of manufacturing an implantable or insertable medical device thatcomprises a polymeric matrix region comprising: (a) a biocompatiblepolymer, (b) at least one therapeutic agent selected from ketorolac andpharmaceutically acceptable salts thereof and (c) a radio-opacifyingagent, wherein said medical device is adapted for implantation orinsertion at a site that is associated with pain or discomfort uponimplantation or insertion, said method comprising: providing acombination comprising said biocompatible polymer, said therapeuticagent and said radio-opacifying agent; extruding said combination; andforming said polymeric matrix from said combination into a single-layermatrix polymer structure, wherein said radio-opacifying agent is bismuthsubcarbonate, and wherein said biocompatible polymer is anethylene-vinyl acetate (EVA) copolymer.
 12. The method of claim 11,wherein forming said polymeric matrix comprises (a) forming an initialblend comprising said biocompatible polymer and said radio-opacifyingagent; (b) combining said initial blend and said therapeutic agent; and(c) forming said polymeric matrix.
 13. The method of claim 12, whereinsaid initial blend is formed using a thermoplastic process.
 14. Themethod of claim 12, wherein said initial blend is formed using anextrusion process.
 15. The method of claim 13, wherein said polymericmatrix is formed using a further thermoplastic process.
 16. The methodof claim 15, wherein said further thermoplastic process is conductedunder conditions such that substantial degradation of said therapeuticagent is avoided.
 17. The method of claim 15, wherein said furtherthermoplastic process is conducted under conditions such thatdegradation of said therapeutic agent is less than 2%.
 18. The method ofclaim 12, wherein said initial blend is formed using a solution process.19. The implantable or insertable medical device of claim 1, wherein theimplantable or insertable medical device is a ureteral stent.
 20. Themethod of claim 11, wherein the implantable or insertable medical deviceis a ureteral stent.
 21. The implantable or insertable medical device ofclaim 9, wherein the implantable or insertable medical device is aureteral stent.
 22. The implantable or insertable medical device ofclaim 1, wherein said medical device is a ureteral stent and wherein thecumulative release of therapeutic agent is in an amount selected from5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, and 99%,relative to the total therapeutic agent in the device, afterimplantation or insertion at said site for a period selected from 1 day,2 days, 4 days, 1 week, 2 weeks, 1 month, 2 months, 4 months, 1 year and2 years.
 23. The device of claim 1, further comprising a lubriciouslayer comprising one or more hydrogels comprising a hydrophilicpolymeric material.